Blockade of A2B adenosine receptor reduces left ventricular dysfunction and ventricular arrhythmias 1 week after myocardial infarction in the rat model

Hao Zhang, Hongyan Zhong, Thomas Everett, Emily Wilson, Roger Chang, Dewan Zeng, Luiz Belardinelli, Jeffrey E. Olgin

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background Remodeling occurs after myocardial infarction (MI), leading to fibrosis, dysfunction, and ventricular tachycardias (VTs). Adenosine via the A2B adenosine receptor (A2BAdoR) has been implicated in promoting fibrosis. Objective To determine the effects of GS-6201, a potent antagonist of the A2BAdoR, on arrhythmogenic and functional cardiac remodeling after MI. Methods Rats underwent ischemia-reperfusion MI and were randomized into 4 groups: control (treated with vehicle), angiotensin-converting enzyme inhibitor (treated with enalapril 1 day after MI), GS-6201-1d (treated with GS-6201 1 day after MI), GS-6201-1w (treated with GS-6201 administered 1 week after MI). Echocardiography was performed at baseline and 1 and 5 weeks after MI. Optical mapping, VT inducibility, and histologic analysis were conducted at follow-up. Results Treatment with the angiotensin-converting enzyme inhibitor improved ejection fraction (57.8% ± 2.5% vs 43.3% ± 1.7% in control; P <.01), but had no effect on VT inducibility. Treatment with GS-6201 improved ejection fraction (55.6% ± 2.6% vs 43.3% ± 1.7% in control; P <.01) and decreased VT inducibility (9.1% vs 68.4% in control; P <.05). Conduction velocities were significantly higher at border and infarct zones in hearts of rats treated with GS-6201 than in those of other groups. The conduction heterogeneity index was also significantly lower in hearts of rats treated with GS-6201. Histologic analysis showed that while both GS-6201 and enalapril decreased fibrosis in the noninfarct zone, only GS-6201 reduced the heterogeneity of fibrosis at the border, which is consistent with its effect on VT reduction. Conclusions Treatment with an A2BAdoR antagonist at 1 week results in the improvement in cardiac function and decreased substrate for VT. The inhibition of fibrogenesis by A2BAdoR antagonists may be a new target for the prevention of adverse remodeling after MI.

Original languageEnglish (US)
Pages (from-to)101-109
Number of pages9
JournalHeart Rhythm
Volume11
Issue number1
DOIs
StatePublished - Jan 2014
Externally publishedYes

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Adenosine A2B Receptors
Left Ventricular Dysfunction
Cardiac Arrhythmias
Ventricular Tachycardia
Myocardial Infarction
Adenosine A2 Receptor Antagonists
Fibrosis
Enalapril
Angiotensin-Converting Enzyme Inhibitors
3-ethyl-1-propyl-8-(1-(3-trifluoromethylbenzyl)-1H-pyrazol-4-yl)-3,7-dihydropurine-2,6-dione
Adenosine
Reperfusion
Echocardiography
Ischemia

Keywords

  • Fibrosis
  • Myocardial infarction
  • Optical mapping
  • Remodeling
  • Ventricular tachycardia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Blockade of A2B adenosine receptor reduces left ventricular dysfunction and ventricular arrhythmias 1 week after myocardial infarction in the rat model. / Zhang, Hao; Zhong, Hongyan; Everett, Thomas; Wilson, Emily; Chang, Roger; Zeng, Dewan; Belardinelli, Luiz; Olgin, Jeffrey E.

In: Heart Rhythm, Vol. 11, No. 1, 01.2014, p. 101-109.

Research output: Contribution to journalArticle

Zhang, Hao ; Zhong, Hongyan ; Everett, Thomas ; Wilson, Emily ; Chang, Roger ; Zeng, Dewan ; Belardinelli, Luiz ; Olgin, Jeffrey E. / Blockade of A2B adenosine receptor reduces left ventricular dysfunction and ventricular arrhythmias 1 week after myocardial infarction in the rat model. In: Heart Rhythm. 2014 ; Vol. 11, No. 1. pp. 101-109.
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AU - Zhong, Hongyan

AU - Everett, Thomas

AU - Wilson, Emily

AU - Chang, Roger

AU - Zeng, Dewan

AU - Belardinelli, Luiz

AU - Olgin, Jeffrey E.

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N2 - Background Remodeling occurs after myocardial infarction (MI), leading to fibrosis, dysfunction, and ventricular tachycardias (VTs). Adenosine via the A2B adenosine receptor (A2BAdoR) has been implicated in promoting fibrosis. Objective To determine the effects of GS-6201, a potent antagonist of the A2BAdoR, on arrhythmogenic and functional cardiac remodeling after MI. Methods Rats underwent ischemia-reperfusion MI and were randomized into 4 groups: control (treated with vehicle), angiotensin-converting enzyme inhibitor (treated with enalapril 1 day after MI), GS-6201-1d (treated with GS-6201 1 day after MI), GS-6201-1w (treated with GS-6201 administered 1 week after MI). Echocardiography was performed at baseline and 1 and 5 weeks after MI. Optical mapping, VT inducibility, and histologic analysis were conducted at follow-up. Results Treatment with the angiotensin-converting enzyme inhibitor improved ejection fraction (57.8% ± 2.5% vs 43.3% ± 1.7% in control; P <.01), but had no effect on VT inducibility. Treatment with GS-6201 improved ejection fraction (55.6% ± 2.6% vs 43.3% ± 1.7% in control; P <.01) and decreased VT inducibility (9.1% vs 68.4% in control; P <.05). Conduction velocities were significantly higher at border and infarct zones in hearts of rats treated with GS-6201 than in those of other groups. The conduction heterogeneity index was also significantly lower in hearts of rats treated with GS-6201. Histologic analysis showed that while both GS-6201 and enalapril decreased fibrosis in the noninfarct zone, only GS-6201 reduced the heterogeneity of fibrosis at the border, which is consistent with its effect on VT reduction. Conclusions Treatment with an A2BAdoR antagonist at 1 week results in the improvement in cardiac function and decreased substrate for VT. The inhibition of fibrogenesis by A2BAdoR antagonists may be a new target for the prevention of adverse remodeling after MI.

AB - Background Remodeling occurs after myocardial infarction (MI), leading to fibrosis, dysfunction, and ventricular tachycardias (VTs). Adenosine via the A2B adenosine receptor (A2BAdoR) has been implicated in promoting fibrosis. Objective To determine the effects of GS-6201, a potent antagonist of the A2BAdoR, on arrhythmogenic and functional cardiac remodeling after MI. Methods Rats underwent ischemia-reperfusion MI and were randomized into 4 groups: control (treated with vehicle), angiotensin-converting enzyme inhibitor (treated with enalapril 1 day after MI), GS-6201-1d (treated with GS-6201 1 day after MI), GS-6201-1w (treated with GS-6201 administered 1 week after MI). Echocardiography was performed at baseline and 1 and 5 weeks after MI. Optical mapping, VT inducibility, and histologic analysis were conducted at follow-up. Results Treatment with the angiotensin-converting enzyme inhibitor improved ejection fraction (57.8% ± 2.5% vs 43.3% ± 1.7% in control; P <.01), but had no effect on VT inducibility. Treatment with GS-6201 improved ejection fraction (55.6% ± 2.6% vs 43.3% ± 1.7% in control; P <.01) and decreased VT inducibility (9.1% vs 68.4% in control; P <.05). Conduction velocities were significantly higher at border and infarct zones in hearts of rats treated with GS-6201 than in those of other groups. The conduction heterogeneity index was also significantly lower in hearts of rats treated with GS-6201. Histologic analysis showed that while both GS-6201 and enalapril decreased fibrosis in the noninfarct zone, only GS-6201 reduced the heterogeneity of fibrosis at the border, which is consistent with its effect on VT reduction. Conclusions Treatment with an A2BAdoR antagonist at 1 week results in the improvement in cardiac function and decreased substrate for VT. The inhibition of fibrogenesis by A2BAdoR antagonists may be a new target for the prevention of adverse remodeling after MI.

KW - Fibrosis

KW - Myocardial infarction

KW - Optical mapping

KW - Remodeling

KW - Ventricular tachycardia

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